This Phase I SBIR proposal is in response to Program Announcement PAR-98-073, "SBIR-AT-NIAID," which targets the development of new HIV-1 therapies using advanced technologies. The human cell surface glycoprotein CD4 is the cellular receptor for the human immunodeficiency virus type l (HIV-1) and binds with high affinity to the HIV-l envelope glycoprotein gpl20. Inhibition of gp120/CD4 interaction as well as gpl20/CD4-mediated virus-to-cell membrane fusion is an important target for therapeutics to treat HIV-1 infection. The goal of this Phase I project is to identify small molecules from combinatorial chemical libraries which specifically inhibit gpl20/CD4 interaction. The recently published crystal structure of gp120 complexed to sCD4 and a monoclonal antibody revealed several extraordinary features that suggest targets for therapeutic intervention. This new information will be used to guide selection of structurally biased combinatorial libraries prepared by Pharmacopeia. The libraries will be screened at Progenics using a proprietary gpl20/CD4 attachment assay. The feasibility of the Phase I project will be demonstrated if at least one compound is identified which broadly inhibits gpl20/CD4 interaction and HIV-I infection and has consistent structure-activity relationships. During the Phase II period, active compounds identified in Phase I will be optimized using the SAR and tested in the best available model systems for the selection of clinical development candidates. The crystal structure of the gp120/CD4 complex revealed the interaction between these two proteins in atomic detail and provided new insights in viral attachment and subsequent membrane fusion. This new structural information, taken together with the power of molecular modeling and combinatorial chemistry, represents the cornerstones for the successful development of a new class of antiretrovirals that target HIV-1 attachment. PROPOSED COMMERCIAL APPLICATIONS: Development of novel compounds for the treatment of HIV-1 infection. This project seeks to develop small-molecule drugs that interrupt HIV-1 attachment to target cells by blocking gpl20/CD4 complex formation. A structure-based approach to identify inhibitors will be pursued, incorporating information from the recently solved crystal structure of the gpl20/CD4 complex together with molecular modeling and combinatorial chemistry.